Endothelial cells require functional FLVCR1a during developmental and adult angiogenesis.

The Feline Leukemia Virus Subgroup C Receptor 1a (FLVCR1a) is a transmembrane heme exporter essential for embryonic vascular development. However, the exact role of FLVCR1a during blood vessel development remains largely undefined. Here, we show that FLVCR1a is highly expressed in angiogenic endothelial cells (ECs) compared to quiescent ECs. Consistently, ECs lacking FLVCR1a give rise to structurally and functionally abnormal vascular networks in multiple models of developmental and pathologic angiogenesis. Firstly, zebrafish embryos without FLVCR1a displayed defective intersegmental vessels formation. Furthermore, endothelial-specific Flvcr1a targeting in mice led to a reduced radial expansion of the retinal vasculature associated to decreased EC proliferation. Moreover, Flvcr1a null retinas showed defective vascular organization and loose attachment of pericytes. Finally, adult neo-angiogenesis is severely affected in murine models of tumor angiogenesis. Tumor blood vessels lacking Flvcr1a were disorganized and dysfunctional. Collectively, our results demonstrate the critical role of FLVCR1a as a regulator of developmental and pathological angiogenesis identifying FLVCR1a as a potential therapeutic target in human diseases characterized by aberrant neovascularization.

El rol actual de los trombolíticos en el tratamiento de la obstrucción de arteria central de la retina / The actual role of thrombolytic treatment in central retinal artery occlusion

Objetivo El propósito de este estudio es determinar la aplicación del tratamiento trombolítico en la obstrucción de la arteria central de la retina (OACR), sus beneficios reales, su seguridad y sus posibles indicaciones. Métodos Realizamos una investigación en las bases de datos de Pubmed, Cochrane y Google Scholar, primero en búsqueda de la efectividad del tratamiento tradicional para la OACR y luego llevamos a cabo una comparación con las nuevas estrategias de terapia que involucran fibrinolíticos intravenosos e intraarteriales. Resultados Mientras que pequeños estudios retrospectivos u observacionales proponen el uso del tratamiento trombolítico, estudios multicéntricos randomizados no pudieron demostrar mejorías visuales significativas con esta nueva terapia. Además, se observó un mayor riesgo de efectos adversos potencialmente amenazantes para la vida de los pacientes que utilizaron el tratamiento trombolítico. Conclusiones Hasta que no existan estudios bien diseñados que demuestren un claro beneficio de la terapia trombolítica para la mejoría visual, y que este beneficio sea contrastado con la frecuencia y severidad de los efectos adversos, no podemos recomendar el tratamiento fibrinolítico para la OACR (AU)

Objective The purpose of this study is to determine the application of thrombolytic treatment in central retinal artery occlusion (CRAO), its real benefit, safety and possible indications for treatment. Methods We searched the PubMed, Cochrane and Google Scholar databases delving first into the effectiveness of the traditional treatment for CRAO, and then comparing them with new treatment strategies with intra venous or intra arterial fibrinolysis. Results Whereas small retrospective and open-label observational trials support the use of thrombolytic therapy, multicenter randomized trials failed to demonstrate a significant visual improvement with this new strategy. Besides that, a greater risk of life threatening adverse event was observed in patients using thrombolytic treatment. Conclusion Until well-conducted clinical trials demonstrate a clear benefit of thrombolytic therapy for improving visual acuity and their benefit are weighted against the frequency and severity of adverse events, we could not recommend fibrinolysis for treating CRAO (AU)

The actual role of thrombolytic treatment in central retinal artery occlusion. / El rol actual de los trombolíticos en el tratamiento de la obstrucción de arteria central de la retina.

OBJECTIVE: The purpose of this study is to determine the application of thrombolytic treatment in central retinal artery occlusion (CRAO), its real benefit, safety and possible indications for treatment. METHODS: We searched the PubMed, Cochrane and Google Scholar databases delving first into the effectiveness of the traditional treatment for CRAO, and then comparing them with new treatment strategies with intra venous or intra arterial fibrinolysis. RESULTS: Whereas small retrospective and open-label observational trials support the use of thrombolytic therapy, multicenter randomized trials failed to demonstrate a significant visual improvement with this new strategy. Besides that, a greater risk of life threatening adverse event was observed in patients using thrombolytic treatment. CONCLUSION: Until well-conducted clinical trials demonstrate a clear benefit of thrombolytic therapy for improving visual acuity and their benefit are weighted against the frequency and severity of adverse events, we could not recommend fibrinolysis for treating CRAO.

Entry of sanfetrinem into human polymorphonuclear granulocytes and its cell-associated activity against intracellular, penicillin-resistant Streptococcus pneumoniae.

The entry of antibiotics into phagocytes is necessary for activity against intracellular pathogens. The ability of sanfetrinem, the first member of a new class of antibiotics, to penetrate human polymorphonuclear granulocytes and its consequences upon subsequent phagocytosis and killing of ingested penicillin-resistant Streptococcus pneumoniae have been evaluated. Sanfetrinem penetrated into human polymorphonuclear leukocytes (PMNs) at all concentrations tested, with cellular concentration/extracellular concentration ratios of 6.6 to 5.03 and 4.21 when sanfetrinem was used at 0.25 to 0.5 and 1 microgram/ml, respectively, within 30 min of incubation. The uptake was complete within 5 min and was not energy dependent, since it was not affected by cell viability, environmental temperature, or the addition of a metabolic inhibitor. At a concentration of one-half the MIC, sanfetrinem significantly enhanced human PMN phagocytosis and increased intracellular bactericidal activity against penicillin-resistant S. pneumoniae. Following preexposure of PMNs to a concentration of one-half the MIC of sanfetrinem, there was a significant increase in both phagocytosis and killing compared with that for the controls, indicating the ability of sanfetrinem to interact with biological membranes and remain active within PMNs. Preexposure of streptococci to sanfetrinem made penicillin-resistant S. pneumoniae more susceptible to the bactericidal mechanisms of human PMNs than untreated organisms.

The antibacterial activity of amoxycillin/clavulanic acid against Staphylococcus aureus ingested by human granulocytes.

The effect of amoxycillin, and amoxycillin/clavulanic acid on the in vitro interaction between human polymorphonuclear cells and a beta-lactamase producing strain of Staphylococcus aureus was investigated. Amoxycillin alone, at half the MIC, significantly inhibited the bacterial uptake by polymorphonuclear (PMN) cells compared with the control; as a consequence the killing of intracellular staphylococci was higher. Clavulanic acid did not have any significant effect upon the activities of phagocytes. The combination amoxycillin/clavulanic acid possesses beneficial properties which result in enhancement of both phagocytosis and microbicidal activity of PMN cells against the beta-lactamase producing strain of S. aureus. A synergic effect between drugs and serum activity was noted.

Effect of rufloxacin upon non-specific immune defences: in-vitro, ex-vivo and in-vivo results.

This study investigated in-vitro, ex-vivo and in-vivo the immunomodulatory effects of rufloxacin. 0.5 MIC of rufloxacin significantly enhanced human macrophage phagocytosis and increased intracellular killing of Klebsiella pneumoniae in vitro. Pre-incubation of K. pneumoniae with rufloxacin made the bacteria more susceptible to both phagocytosis and intracellular killing by human macrophages than control organisms. Following pre-exposure of macrophages to 0.5 MIC of rufloxacin, there was a significant increase in the intracellular killing of K. pneumoniae compared with the controls, indicating the ability of rufloxacin to cross biological membranes and to remain active within phagocytes. Ex-vivo experiments show that iv administration of rufloxacin in mice lead to an increase in both phagocytic and microbicidal intracellular activity by phagocytes. In-vivo models of experimental infections showed that prophylactic administration of rufloxacin increased the survival of mice after challenge with Candida albicans.

Effect of ceftriaxone on the phagocytosis and intracellular killing of Staphylococcus aureus by human macrophages.

The efficacy of an antimicrobial agent in the treatment of infections depends upon the interactions of bacteria, antibiotic and phagocytes. The influence of ceftriaxone on the phagocytic and bactericidal activity of human macrophages in vitro and ex vivo was investigated. At concentrations one-half the minimum inhibitory concentration (1/2 x MIC) the antibiotic caused in vitro a significant enhancement of phagocytosis and a reduction in the survival of intracellular Staphylococcus aureus. The distinction between any effect of ceftriaxone on the staphylococci and the macrophages was made by exposure of each of them to the antibiotic before they were incubated together. The results suggest that ceftriaxone may have a direct positive action on macrophages, possibly by interfering with the cellular membrane functions and hence enhancing engulfment of bacteria. The ex vivo data seem to corroborate this hypothesis.

[In vitro activity of several antibiotics on pathogenic micro-organisms isolated from the lower respiratory tract]. / Attivita' in vitro di alcuni antibiotici su microrganismi patogeni isolati dalle basse vie respiratorie.

Lower respiratory tract infections are clinically important, because of their high incidence, as well as the significant morbidity they cause. Hence the great importance to diagnose the etiology of these infections and treat the patient with selective therapy. In this study 367 bacteria isolated from lower respiratory tract were identified (253 Gram negative and 114 Gram positive) and tested towards augmentin, ceftriaxone, lomefloxacin, ciprofloxacin, ofloxacin and erythromycin. The in vitro activity of such antibiotics against the clinical isolates was compared.

The entry of meropenem into human macrophages and its immunomodulating activity.

The uptake of meropenem by human macrophages and its consequences upon subsequent phagocytosis and killing of intracellular staphylococci has been studied. The cellular to extracellular concentration ratios (C/E) of meropenem were always high (range 3-12) at extracellular concentrations ranging from 0.125 to 1 mg/L. The uptake was not energy-dependent, being similar when viable and formalin-killed cells were used and was influenced neither by environmental temperature nor by the addition of a metabolic inhibitor. Meropenem at half the MIC caused a significant enhancement of phagocytosis and a reduction in the survival of intracellular Staphylococcus aureus. Pre-exposure of either staphylococci or macrophages to sub-MIC concentrations of meropenem led to an increase in uptake of bacteria and intracellular bactericidal activity by macrophages.

Enhanced Staphylococcus aureus susceptibility to immunodefences induced by sub-inhibitory and bactericidal concentrations of imipenem.

Recent evidence suggests that the selection of an antibiotic for the treatment of infection should take into account not only the drug's antimicrobial activity but also the way in which it interacts with host defence mechanisms, since this may influence the response to infection. In this study we have investigated the effects of imipenem on the activities of human macrophages against Staphylococcus aureus. Bacterial susceptibility to phagocytosis and intracellular killing were determined after S. aureus and macrophages were incubated both simultaneously with sub-inhibitory and bactericidal concentrations of imipenem and following pre-exposure of the organisms and the macrophages individually to the same concentrations of imipenem. At both concentrations and under both circumstances, imipenem potentiated the phagocytic and microbicidal activities of the macrophages.

[Urinary infection. II. Comparative in vitro activities of several antibiotic drugs against Gram-positive bacteria]. / Infezioni urinarie. II. Attività comparativa in vitro di alcuni chemioantibiotici nei confronti di batteri gram positivi.

In this study the in vitro susceptibility of 1,009 Gram-positive strains isolated from 4,505 positive urocultures was evaluated towards the following chemotherapeutic agents: oxacillin, ampicillin, amoxicillin + clavulanic acid, imipenem, cefalotin, cefotaxime, amikacin, gentamicin, ciprofloxacin, pefloxacin, clindamycin, erythromycin, vancomycin, rifampicin, tetracycline and chloramphenicol. The results indicate that vancomycin is the most active antibiotic against all the strains, including enterococci often involved in serious infections caused by invasive techniques.

[Urinary infection. I. Comparative in vitro activities of several antibiotic drugs against Gram-negative bacteria]. / Infezioni urinarie. I. Attivita' comparativa in vitro di alcuni chemioantibiotici nei confronti di batteri gram negativi.

The in vitro activity of imipenem against 3,496 Gram-negative strains isolated from 4,505 positive urocultures was determined. The effectiveness of imipenem was then compared with that of ampicillin, amoxycillin + clavulanic acid, ticarcillin, piperacillin, aztreonam, cefalotin , ceftazidime, cefoxitin, cefotaxime, norfloxacin, ciprofloxacin, amikacin, gentamicin, tobramycin, trimethoprim + sulfamethoxazole. Imipenem was active against all isolates, including Pseudomonas spp. known to account for a large portion of nosocomial infections and resistance to antibacterial drugs.

Pefloxacin and immunity: cellular uptake, potentiation of macrophage phagocytosis and intracellular bioactivity for Klebsiella pneumoniae.

Antibiotic potentiation of host defence mechanisms may be of potential clinical importance in the outcome of infections. Therefore the effect of pefloxacin upon the interaction of in vitro of human macrophages with Klebsiella pneumoniae, by assays of antibiotic cellular uptake, bacterial phagocytosis and intracellular killing, was examined. The results indicated that pefloxacin was well concentrated by phagocytes at all the concentrations tested. The uptake proceeded rapidly and was not affected either by cell viability or physiological environmental temperature. Synergistic phagocytosis and intracellular killing of K. pneumoniae was observed in the presence of macrophages and subinhibitory concentrations (one-half MIC) of pefloxacin. Pretreatment of bacteria with pefloxacin led to an increase in both bacterial uptake and microbicidal activity of phagocytes. Exposure of the macrophages to pefloxacin did not affect any phagocyte functions.